Age-related differences in striatal dopamine D1 receptors mediate subjective drug effects
Authors: Peter Manza, Ehsan Shokri-Kojori, Şükrü Barış Demiral, Rui Zhang, Evan Dennis, Allison Johnson, Leah Vines, Diana Sotelo, Dardo Tomasi, Gene-Jack Wang, Nora D. Volkow
Journal: Journal of Clinical Investigation (2022)

To the Editor: The brain's dopamine system is critical for cognition, reward, and motivation.It plays a crucial role in the reinforcing effects of drugs with addiction potential as well as in some of their therapeutic effects (e.g., stimulants, such as methylphenidate [MP]) (1).Importantly, aging is associated with declines in key proteins involved in dopamine signaling, including D1-and D2-like dopamine receptors (D1Rs and D2Rs) and dopamine transporters (2), and there is some evidence that elderly individuals are less sensitive to the subjective effects of stimulant drugs than young adults (3).This opens the possibility that age-related declines in dopamine signaling in brain reward regions affect sensitivity to the positive reinforcing effects of drugs, a key risk factor for the development of a substance use disorder (SUD) (4).This would help explain why substance use and SUD rates are much lower among elderly individuals compared with those among younger adults (5).If specific brain markers of dopamine signaling are tied to aging and drug effects, then this information could be leveraged to better understand individual differences in vulnerability to substance misuse and SUD.Using PET imaging, we collected measures of D1Rs and D2Rs and estimates of MP-induced dopamine increases to study the effect of age on the subjective experience of MP in healthy adults.We hypothesized that striatal D1R would show a stronger association with subjective MP effects than striatal D2 and that striatal D1R availability would mediate the link between age and subjective MP effects.Thirty-six healthy adults (23 men and 13 women; age, 22-64 years) participated (for detailed demographics, see Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/JCI164799DS1).All participants provided written informed consent prior to participation.The NIH IRB approved the study.PET scans measured D1R availability with [ 11 C]NNC-112 and D2R availability with [ 11 C]raclopride.All [ 11 C]NNC-112 scans were conducted in a baseline state.[ 11 C]raclopride scans were conducted on 2 separate days: (a) 1 hour after administration of an oral placebo pill and (b) 1 hour after administration of 60 mg oral MP to quantify dopamine increases by comparing changes in D2R availability with placebo scans (6).Before [ 11 C]raclopride scans, drugs were administered in a single-blind design, and session order was counterbalanced.All participants underwent all 3 PET scans.Periodically throughout the sessions, participants were asked to rate, on a scale of 1 to 10, several questions about their subjective experience of drug reward in response to MP.We characterized associations among D1R, D2R, and dopamine increases with age and subjective drug effects at the voxel level and at the region-of-interest (accumbens and dorsal striatum) level.We then performed mediation analysis, hypothesizing that accumbens D1R would mediate the negative association between age and subjective drug effects.For all analyses, a P value of less than 0.05 was considered significant.For more details, see Supplemental Methods.